Neoplastic Disease
Neoplasia is the relatively autonomous proliferation of cells, whereby cells partially or totally escape physiological control mechanisms that ordinarily constrain cell proliferation and regulate cell differentiation. The proliferation of normal cells is believed regulated by growth-promoting proto-oncogenes counterbalanced by growth-constraining tumor-suppressor genes. Mutations that potentiate the activities of proto-oncogenes can create the oncogenes that force the deregulated growth of neoplastic cells. Conversely, genetic lesions that inactivate tumor suppressor genes, generally through mutation(s) that lead to a cell being homozygous for the inactivated tumor suppressor allele, can liberate the cell from the normal replicative constraints imposed by these genes. Often, an inactivated tumor suppressor gene in combination with the formation of an activated oncogene (i.e., a proto-oncogene containing an activating structural or regulatory mutation) can yield a neoplastic cell capable of essentially unconstrained growth (i.e., a transformed cell).
Many pathological conditions result, at least in part, from aberrant control of cell proliferation, differentiation, and/or apoptosis. For example, neoplasia is characterized by a clonally derived cell population which has a diminished capacity for responding to normal cell proliferation control signals. Oncogenic transformation of cells leads to a number of changes in cellular metabolism, physiology, and morphology. One characteristic alteration of oncogenically transformed cells is a loss of responsiveness to constraints on cell proliferation and differentiation normally imposed by the appropriate expression of cell growth regulatory genes.
The precise molecular pathways and secondary changes leading to malignant transformation for many cell types are not entirely clear.
Oncogenic transformation of cells leads to a number of changes in cellular metabolism, physiology, and morphology. One characteristic alteration of oncogenically transformed cells is a loss of responsiveness to constraints on cell proliferation and differentiation normally imposed through one or more signalling pathway(s) which comprise proteins encoded by proto-oncogenes. For example, proteins encoded by ras genes serve as essential transducers of diverse physiological signals, and mutationally altered ras gene products are important contributors to the neoplastic phenotype. The 21 kilodalton protein encoded by the ras.sup.H gene, referred to as p21.sup.ras, is involved in the signal transduction of various factors controlling cell proliferation, differentiation, and oncogenesis.